Pralatrexate, chemically known as “(2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]-amino]pentanedioic acid”, also known as “10-Propargyl-10-deazaminopterin” or “PDX”, is a compound which has been tested and found useful in the treatment of cancer. In its racemic form, 2S)-2-[[4-[(1RS)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]-pentanedioic acid has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory peripheral T-cell lymphoma.
Pralatrexate, represented by Formula (I), was first disclosed in Journal of Medicinal Chemistry. 36: 2228-2231 (1993) by DeGraw et al., and subsequently in U.S. Pat. No. 5,374,726 and U.S. Pat. No. 5,354,741.

DeGraw et al., publication, U.S. Pat. No. 5,374,726 and U.S. Pat. No. 5,354,741 disclose method for the synthesis of Pralatrexate of Formula (I), comprising alkylation of homoterephthalic acid dimethyl ester with propargyl bromide using Potassium Hydride, which is further coupled with 2,4-diamino-6-bromomethylpteridine in presence of Potassium Hydride followed by hydrolysis in presence of NaOH in 2-methoxyethanol-water mixture and decarboxylation at high temperature in DMSO and subsequent coupling with L-glutamic acid diethyl ester using t-butyl chloroformate and a base, and finally hydrolysis of the product with NaOH in 2-methoxyethanol-water mixture to give Pralatrexate of Formula (I). The process is outlined below as synthetic Scheme-1.

The methods disclosed in DeGraw et al., publication, U.S. Pat. No. 5,374,726 and U.S. Pat. No. 5,354,741 suffer from the following disadvantages, which are outlined below:    (i) Use of pyrophoric Potassium hydride in the initial alkylation step and the subsequent coupling step.    (ii) Amide formation in the penultimate step by use of a hazardous chloroformate reagent.    (iii) The final product has a purity of ˜95% and is contaminated with the 10-deazaminopterin impurity to the level of 4%, which affects the final quality of Active Pharmaceutical ingredient (API) and does not meet the Pharmacopeial specifications.    (iv) Use of 2-methoxyethanol in the last step which is classified under guideline of International Conference on Harmonisation of Pharmaceutical for Human USE (ICH) as a Class-2 solvent, with a maximum daily exposure limit of 50 ppm.    (v) Extensive use of column chromatography during the method adding to the cost of manufacture.    (vi) Low yield of the final Pralatrexate (˜5.5%).
U.S. Pat. No. 6,028,071 discloses a process for the preparation of Pralatrexate of Formula (I) comprising coupling of homoterephthalic acid dimethyl ester with propargyl bromide using NaH in THF, further coupling of the product with 2,4-diamino-6-bromomethylpteridine using NaH in DMF, followed by hydrolysis with a base in 2-methoxyethanol-water mixture, and decarboxylation at elevated temperatures at 115-120° C. in DMSO, and finally coupling of the product with L-glutamic acid dimethyl ester using benzotriazole-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP) and triethylamine in DMF, and finally hydrolysis with NaOH in methanol-water mixture to yield Pralatrexate. The process is outlined below as synthetic Scheme-2.

The process disclosed in U.S. Pat. No. 6,028,071 suffer from the following disadvantages outlined below                (i) Use of sodium hydride in the initial alkylation step and the subsequent coupling step.        (ii) Using benzotriazole-1-yloxytris(dimethylamino) phosphonium hexafluoro phosphate (BOP) in coupling reaction that liberates Hexamethylphosphoramide (HMPA), which is carcinogenic        (iii) Extensive column chromatography during the process adding to the cost of manufacture        (iv) Quality of the API obtained by this process is only ˜98%.        (v) Low yield of Pralatrexate is obtained (2.06%).        (vi) In the propargylation step the ratio of α-monopropargyl homoterephthalic acid dimethyl ester to α-monopropargyl homoterephthalic acid dimethyl ester is not less than 75:25.        
US 20110190305 relates to optically pure diastereomers of 10-propargyl-10-deazaminopterin, in particular the two (R,S) diastereomers about the C10 position. None of the prior art discloses a process for preparing substantially pure Pralatrexate. When the present inventors practiced the invention disclosed in U.S. Pat. No. 6,028,071 to ascertain the purity of Pralatrexate, they found the content of individual diastereomers at the C10 position to be 50±3.66%.
Typically, drug substances that are racemic, preferably contain at least one chiral centre resulting in two diastereomers of equal proportion. Any substantial change in diastereomeric ratio may lead to loss of racemisation and may result in a drug substance with undesirable therapeutic effect. Consequently, there was a need to obtain a substantially pure racemic Pralatrexate, in particular the two diastereomers about the C10 position, wherein the content of each diastereomer is 50±0.6%. The process described within the instant invention resolves this issue.
Accordingly, there is a need in the art for improved methods for preparation of Pralatrexate which is a simple, convenient, economical, industrially viable commercial process and restricts the use of hazardous and expensive reagents and solvents and moreover, utilizes a simple and less laborious purification method, restricting the use of expensive column chromatography and results in the formation of Pralatrexate, in particular Pralatrexate obtained in high yields and of Pharmacopoeial grade having a purity.
In their endeavor to provide an improved process for manufacture of Pralatrexate of Formula (I), the present inventors found that most, if not all of the limitations of the prior art could be addressed through utilization of:                a) Novel intermediates for synthesis of the object compounds;        b) Less expensive, less hazardous reagents and solvents; and        c) Novel and simple purification methods, restricting the use of column chromatography.        d) Highly pure Pralatrexate of purity not less than 99% and overall high yield of not less than 11%.        e) Cost effective and robust process.        